Severe neuronal loss characterizes Alzheimer's disease (AD); however, the mechanisms by which neurons die remain elusive. Elucidating the mechanisms underlying neuronal loss in AD will be invaluable to the development of new therapeutic approaches. In this application, we focus on necroptosis, a programmed form of necrosis, triggered by receptor-interactive protein kinases (RIPK) 1 and 3 and executed by the mixed lineage kinase domain-like (MLKL) protein. Upon activation by multiple inflammatory stressors, RIPK1 binds to RIPK3 to form a multiprotein complex known as necrosome, which is sufficient for necroptosis activation. The necrosome forms on the membrane of autophagosomes highlighting a close interaction between necroptosis and autophagy. We provide compelling evidence showing that necroptosis is activated in AD where it may contribute to neurodegeneration. Consistently, we and others have reported that in AD brains RIPK1 is upregulated in microglia and neurons. We also generated a causal gene regulatory network to model RIPK1 interactions in AD and found that RIPK1 activity may explain a significant portion of transcriptomic changes in AD. We further show that pharmacologically decreasing RIPK1 activity reduces neuronal loss in 5xFAD mice. In this application, we will test the overarching hypothesis that RIPK1 contributes to neurodegeneration in AD by activating necroptosis. Specific Aim 1 will identify the role of microglial and neuronal RIPK1 in AD. Specific Aim 2 will determine the mechanisms of RIPK1-mediated necroptosis activation in AD. Specific Aim 3 will identify new strategies to block RIPK1-mediated neurodegeneration. Impact: The mechanisms by which neurons die are still unknown. We propose that RIPK1-mediated necroptosis is a crucial mechanism of neurodegeneration in AD and propose experiments to dissect the role of this protein kinase in this insidious disorder. Our results will open new opportunities for research and interventions for AD and will identify new highly translational compounds to block necroptosis activation.